title: Nitric oxide prevents axonal degeneration by inducing HIF-1-dependent expression of erythropoietin.
abstract: Nitric oxide (NO) is a signaling molecule that can trigger adaptive (physiological) or maladaptive (pathological) responses to stress stimuli in a context-dependent manner. We have previously reported that NO may signal axonal injury to neighboring glial cells. In this study, we show that mice deficient in neuronal nitric oxide synthase (nNOS-/-) are more vulnerable than WT mice to toxin-induced peripheral neuropathy. The administration of NO donors to primary dorsal root ganglion cultures prevents axonal degeneration induced by acrylamide in a dose-dependent manner. We demonstrate that NO-induced axonal protection is dependent on hypoxia-inducible factor (HIF)-1-mediated transcription of erythropoietin (EPO) within glial (Schwann) cells present in the cultures. Transduction of Schwann cells with adenovirus AdCA5 encoding a constitutively active form of HIF-1α results in amelioration of acrylamide-induced axonal degeneration in an EPO-dependent manner. Mice that are partially deficient in HIF-1α (HIF-1α+/-) are also more susceptible than WT littermates to toxic neuropathy. Our results indicate that NO→HIF-1→EPO signaling represents an adaptive mechanism that protects against axonal degeneration.
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Sanjay C
authors.initials: SC
authors.lastname: Keswani
authors.forename: Marta
authors.initials: M
authors.lastname: Bosch-Marcé
authors.forename: Nicole
authors.initials: N
authors.lastname: Reed
authors.forename: Angela
authors.initials: A
authors.lastname: Fischer
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.forename: Ahmet
authors.initials: A
authors.lastname: Höke
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000096:biosynthesis* / Q000235:genetics; D005727:Ganglia, Spinal / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000235:genetics / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052248:Nitric Oxide Synthase Type I / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D014161:Transduction, Genetic
chemical_list: D051793:Hypoxia-Inducible Factor 1; D020030:Nitric Oxide Donors; D004921:Erythropoietin; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse